SotoRasib 是一种有效的 KRas G12C 共价抑制剂，用 AMG 510 治疗导致 KRasG12C 肿瘤消退，并提高了化疗和靶向药物的抗肿瘤功效。

AMG-510 is a potent KRAS G12C covalent inhibitor, treatment with AMG 510 led to the regression of KRASG12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents.

AMG 510 inhibited SOS-catalyzed nucleotide exchange of recombinant mutant KRASG12C/C118A but had minimal effect on KRASC118A, which is wildtype at position 12.?In cellular assays, AMG 510 covalently modified KRASG12C and inhibited KRASG12C signaling as measured by phosphorylation of ERK1/2 (p-ERK) in all KRAS p.G12C-mutant cell lines tested but did not inhibit p-ERK in cell lines with various other KRAS mutations.?AMG 510 also selectively impaired viability of KRAS p.G12C mutant cell lines but did not affect cell lines with other KRAS mutations[1].

In mice with xenografts of human tumour cells, AMG 510 significantly inhibited the growth of MIA PaCa-2 T2 and NCI-H358 tumours at all doses,and regression of tumours was observed at higher doses .The dose of AMG 510 that was required to achieve the regression of MIA?PaCa-2 T2 tumours was at least 3.3-fold lower than ARS-1620.?Plasma exposures above the cellular IC90 of p-ERK for more than 2 h resulted in tumour regression .?AMG 510 also inhibited the growth of KRASG12C-mutant patient-derived xenografts .?By contrast, AMG 510 treatment had no effect on KRASG12V tumour growth .?In immune-competent mice, AMG 510 resulted in regression of CT-26?KRASG12C tumours, a mouse syngeneic tumour model generated by CRISPR technology.?Two of the ten mice in the 100 mg/kg group had no detectable tumours at the end of the study (day 29).?However, regression of the tumours lacked durability, possibly owing to incomplete inhibition of p-ERK .?Therefore, a dose of 200 mg/kg of AMG 510 was evaluated, resulting in near-complete inhibition of p-ERK ?and durable cures in eight out of ten mice, in which AMG 510 plasma levels were just below the cellular IC90 .?Intriguingly, in the same tumour model but in mice that lacked T cells, AMG 510 induced regression but not cures, suggesting that the immune system drives cures in immunecompetent mice [2].

T7328

C30H30F2N6O3

560.59

AMG-510

DMSO:50 mg/mL (89.19 mM)
Powder: -20°C for 3 years
In solvent: -80°C for 2 years